Other Hydrazine Derivative Drugs
There are also cases where other hydrazine derivative drugs, such as the MAOIantidepressantiproniazid, are associated with liver damage.Phenelzine has been associated with abnormal liver tests. Toxic effects can develop from antibiotics.
Examples include alpha-Amanitin containing mushrooms, kava, and aflatoxin producing molds. Pyrrolizidine alkaloids, which occur in some plants, can be toxic. Green tea extract is a growing cause of liver failure due to its inclusion in more products.
Drugs continue to be taken off the market due to late discovery of hepatotoxicity. Due to its unique metabolism and close relationship with the gastrointestinal tract, the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and the spleen via portal veins that bring drugs and xenobiotics in near-undiluted form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process.
Who Is At Risk For Drug
The risk for drug-induced hepatitis varies with each medicine.
You may be at higher risk for drug-induced hepatitis if you:
- Have liver disease, such as from long-term alcohol use, HIV, or viral hepatitis.
- Drink alcohol and take medicines at the same time.
- Are older.
- Pale gray or clay-colored stools
- Yellowing of the skin and eyes
The symptoms of drug-induced hepatitis may look like other health problems. Always see your healthcare provider to be sure.
Drug Metabolism In Liver
The human body subjects most, but not all, compounds to various chemical processes to make them suitable for elimination. This involves chemical transformations to reduce fat solubility and to change biological activity. Although almost all tissues in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in the liver is the principal “metabolic clearing house” for both endogenous chemicals and exogenous substances . The central role played by liver in the clearance and transformation of chemicals makes it susceptible to drug-induced injury.
Drug metabolism is usually divided into two phases: phase 1 and phase 2. Phase 1 reaction is generally speaking to prepare a drug for phase 2. However, many compounds can be metabolized by phase 2 directly or be excreted without any phase 2 reactions occurring. Phase 1 reaction involves oxidation, reduction, hydrolysis, hydration and many other rare chemical reactions. These processes tend to increase water solubility of the drug and can generate metabolites that are more chemically active and/or potentially toxic. Most of phase 2 reactions take place in cytosol and involve conjugation with endogenous compounds via transferase enzymes. Phase 1 are typically more suitable for elimination.
- 1. Genetic diversity:
- 2. Change in enzyme activity:
- 3. Competitive inhibition:
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New Kids On The Block
Tumor Necrosis Factor Antagonists
Tumor necrosis factor antagonists are a class of biological response modifiers that are essential for the treatment for a variety of inflammatory and autoimmune diseases. To better define toxicity of the TNF- antagonists, 34 cases of liver injury were described in detail in a recent review. Most cases were due to infliximab, reflecting the fact that this drug has been in clinical use the longest and that it is the most commonly used TNF- antagonist. The remaining cases were due to etanercept and adalimumab .
The most common pattern is an acute hepatocellular injury followed by a mixed pattern of injury 1 case was characterized by prolonged cholestasis. In two-thirds of cases, the hepatocellular injury was autoimmune in nature as evidenced by presence of serum antinuclear and/or smooth muscle antibodies. Of these cases, almost 90% of those that were subjected to biopsy showed histologic features of autoimmunity. Although the median latency period for all patients was 13 weeks, 20% of patients showed latency periods longer than 24 weeks. Patients with autoimmune features had disease later than those without these features . Those who did not have autoimmune features showed a mixed pattern of injury with levels of alanine aminotransferase that were lower than for those who had autoimmune features . Bilirubin was significantly elevated in approximately one-third of the patients.
Diagnosis Of Dili By Expert Consult System Of The Dilin
The US DILIN created a structured expert opinion approach to assess causality in DILI. A 65-page case report form was created from the patients’ charts to include complete clinical history, serial laboratory tests, history of previous liver disease, alcohol ingestion, serology for viral and autoimmune hepatitis, and serum levels of ceruloplasmin, -1 antitrypsin, ferritin, and iron. From this detailed report, an abbreviated case report form was created, which along with a detailed case summary was presented for review. The review panel consisted of 3 hepatologists who were experts in the field of DILI. Each hepatologist reviewed the case individually and assigned a causality score on a 5-point scale . Each reviewer also assessed the case on RUCAM scale.
It was found that the DILIN structured expert opinion process was more likely to assign causality to a drug than the RUCAM scale. Although there was greater interobserver agreement with the DILIN expert consult system than with the RUCAM scale, interobserver variation was considerable within both systems and correlation between the 2 adjudication methods was weak.
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In Most Cases Resolution Of Drug
Liver enzyme levels usually decrease within days to weeks, with less than 10% of patients having chronic disease 1 year later., In cases of severe elevation of liver enzyme levels , clinical signs of liver failure, or if improvement is not seen within the expected time frame, specialist consultation and investigations for alternative causes or complications of drug-induced liver injury should be pursued.
Pathophysiology And Mechanisms Of Drug
The pathophysiologic mechanisms of hepatotoxicity are still being explored and include both hepatocellular and extracellular mechanisms. The following are some of the mechanisms that have been described:
Drug toxicity mechanisms
The classic division of drug reactions is into at least two major groups, drugs that directly affect the liver and drugs that mediate an immune response, as follows:
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Clinical And Pathological Manifestations Of Drug
Drug hepatotoxicity manifests with clinical signs and symptoms caused by an underlying pathological injury. The clinical presentation may or may not suggest the underlying liver injury, and therefore, the types of injuries are sometimes described separately. Some drugs usually cause one clinical and pathologic injury and other drugs can cause a variety of injuries, often making the diagnosis more challenging.
Natural History Of Dili And Hys Law
In the American DILIN, the presentation of DILI was with jaundice in 70% of cases. Most recovered after drug withdrawal however, 17% progressed to chronic DILI and 10% needed a liver transplant and/or died. Mortality increased to 44% in the presence of Stevens-Johnson syndrome. Compared with those with cholestatic DILI, those with hepatocellular DILI were more likely to require a liver transplant and have fatal injury . Furthermore, use of non-body building HDS was associated with a significantly higher need for liver transplant compared with conventional drugs . Worryingly, 7% of cases were attributed to HDS during the first 2 years of the American DILI registry compared with 20% 10 years later. The American Acute Liver Failure Study Group also recently reported that the prevalence of DILI-ALF/acute liver injury cases due to HDS increased between 19982007 and 20072015 . The HDS group had higher transplantation rates and lower transplant-free survival compared with those receiving conventional drugs.
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Clinical Characteristics Of Drug
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The liver is the principle organ for drug metabolismand transformation. It not only processes the three majormetabolites but is also an important organ for drugs and drugmetabolism. Drug-induced liver injury refers to a diseasecaused by hepatotoxic injury induced by drugs or their metabolitesor due to hepatic hypersensitivity to drugs and their metabolitesduring medication. In recent years, with the extensive use of drugsand the accelerated research of novel drugs, the different types ofclinical drugs have been continuously increasing and the incidenceof DILI has been rising year by year. According to World HealthOrganization statistics, DILI has risen as the 5th leadingcause of death worldwide. Approximately 50% of liver failurepatients receiving liver transplantation every year havedrug-induced liver failure, which prompts the need for artificialliver and liver transplantation and even causes death .However, the disease is often undiagnosed or misdiagnosedclinically because of diagnostic difficulties caused by lack oflaboratory specific serological markers.
Herbal Or Traditional Remedies
Herbal remedies are widely used for a multitude of purposes and evidence about their hepatotoxicity is accumulating. Although the use of herbal products has been consistently rising, no regulatory guidelines or standards are issued for their composition., These factors make it difficult to clearly establish their hepatic toxicities. A notable case of herbal toxicity is reported for HerbalifeÂ® products. Interestingly, Herbalife ingestion has resulted in different patterns of liver injury including one case of fulminant hepatic failure. Further research revealed that contamination with Bacillus subtilis was thought to be responsible for the liver toxicity of Herbalife. Surprisingly, Spirulina, taken for its broad range of protective effects, was also recorded as the culprit for one case of DILI.
Several other more common examples of liver injury due to herbal compounds are provided in . Further complicating the identification of individual toxic components, alternative medicine frequently employs mixtures of several components. For example, acute hepatitis and liver failure were reported for LipoKinetix, a weight loss product containing norephedrine, caffeine, yohimbine, diiodothyronine and sodium usniate, leading to its withdrawal from the US market in 2001., Chinese herbal medicines comprised of multiple compounds have been shown to result in liver injury for example, Dai-Saiko-To and Sho-Saiko-To can induce acute hepatitis.â
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Natural Killer T Cells
Natural killer T cells, a unique subset of T cells, expressing both NK cell receptors and T cell receptors, are MHC class Ilike molecules, CD1d-restricted and glycolipid antigen reactive , and bridge innate and acquired immunity , and are closely related to immune liver injury . Distinct from conventional T lymphocytes, NKT cells preferentially taking the liver as their home, play a pathogenic role in various types of liver disease , secrete cytokines like IFN-, IL-4, and IL-17, and regulate the balance of pro- and anti-inflammatory responses in liver diseases . One case report on analyzing the hepatic and peripheral blood lymphocytes in two patients with drug-induced fulminant hepatic failure indicated that NKT cells might be involved in hepatic injury . Studies have found that NKT cells are dominantly releasing IFN- and recruiting neutrophils and macrophages, leading to TP-induced liver injury . However, NKT cells are not only beneficial in APAP-mediated acute liver injury but also can limit inflammatory cytokine secretion because of type I and II cytokines secretion, making them both protective and harmful.
What Causes Toxic Hepatitis
Toxic hepatitis is usually caused by exposure to certain organic chemicals or solvents, certain medications, drugs or alcohol.
Many chemicals and drugs can cause liver damage. However, people respond differently to different medications. Some people may have an adverse reaction to certain drugs and can suffer liver damage, while others may not. Excessive drinking that causes liver damage can make the harmful effects of drug or chemical exposure worse.
Types of toxic hepatitis include:
- Chemical-induced hepatitis: Exposure to toxic chemicals in the workplace, such as organic chemicals and solvents, is a common cause of toxic hepatitis. Exposure can occur through ingesting a chemical, breathing it in, or through contact with the skin.
- Drug-induced hepatitis: Many prescription and over-the-counter medications may cause liver toxicity or hepatitis , including:
- Dark-colored urine
- Fluid in the abdomen
It may take days, weeks or even months for symptoms to appear after exposure to the chemicals or drugs. Symptoms may be similar to those of other liver disorders.
In chronic cases of toxic hepatitis, extensive liver damage, such as cirrhosis may occur. The patient may also develop severe liver failure, which can be life-threatening.
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Diagnosis Requires Exclusion Of Alternate Causes
Drug-induced liver injury can be particularly difficult to distinguish from autoimmune hepatitis because antibodies seen in this kind of hepatitis may also be positive in drug-induced liver injury. The Roussel Uclaf Causality Assessment Method score is a clinical decision tool to help determine the probability of drug-induced liver injury.
The Role Of Liver Biopsy In Idiosyncratic Dili
Liver biopsy is not required in the clinical evaluation of severe, idiosyncratic DILI and is performed in less than half of suspected cases, including those enrolled in formal studies. However, when performed, the liver biopsy provides valuable information on the nature and severity of liver injury, the possible pathogenesis, and the expected clinical outcome. In addition, the liver biopsy may guide therapy, for example, the finding of drug-induced autoimmune hepatitis may call for treatment with steroids. Above all, a liver biopsy helps to rule out competing causes of liver injury, an essential component in the diagnosis of DILI. In our tertiary care referral center , we receive approximately 25 clinical cases per year that carry a primary diagnosis of DILI, and approximately 40% of those cases were subjected to biopsy as part of the clinical evaluation.
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Clinical Course And Diagnosis Of Drug Induced Liver Disease
The clinical symptoms, signs and patterns of liver test abnormalities of drug induced liver injury can mimic virtually any form of liver disease from acute viral hepatitis to gall stone disease with biliary obstruction, acute fatty liver and even chronic hepatitis and cirrhosis. There are no specific findings or laboratory tests that definitely prove that a suspected drug, nutritional supplement or herbal product is the cause of the injury. Drug induced liver injury is a diagnosis of exclusion and relies upon clinical judgment and knowledge about the potential of the agent to cause liver injury versus the likelihood that other forms of liver diseases are the cause. For some medications, the pattern of clinical presentation and liver test abnormalities strongly suggest that the drug is the cause of the liver injury, but ultimately the more common causes of liver disease must be ruled out before a drug is considered the likely cause.
In judging the likelihood of drug induced liver disease, six features are important:
- the onset after starting the drug: time to onset
- the recovery after stopping the drug: time to recovery
- the clinical pattern: injury pattern and clinical phenotype
- exclusion of other causes of liver injury
- whether the drug is a known cause of liver injury
- response to reexposure, whether inadvertent or intentional
Who Should Be Tested
Testing for hepatitis A is not routinely recommended.
CDC recommends hepatitis B testing for:
- Men who have sex with men
- People who inject drugs
- Household and sexual contacts of people with hepatitis B
- People requiring immunosuppressive therapy
- People with end-stage renal disease
- People with hepatitis C
- People with elevated ALT levels
- Pregnant women
- Infants born to HBV-infected mothers
CDC recommends hepatitis C testing for:
- All adults aged 18 years and older
- All pregnant women during each pregnancy
- About 24,900 new infections each year
- About 22,600 new infections in 2018
- Estimated 862,000 people living with hepatitis B
- About 50,300 new infections in 2018
- Estimated 2.4 million people living with hepatitis C
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Elevated Blood Levels Of Liver Enzymes
Many drugs cause mild elevations in blood levels of liver enzymes without symptoms or signs of hepatitis. AST, ALT, and alkaline phosphatase are enzymes that normally reside within the cells of the liver and bile ducts. Some drugs can cause these enzymes to leak from the cells and into the blood, thus elevating the blood levels of the enzymes. Examples of drugs that more commonly cause elevations of liver enzymes in the blood include the statins some antibiotics, some antidepressants , and some medications used for treating diabetes, tacrine , aspirin, and quinidine .
Since these patients typically experience no symptoms or signs, the elevations of liver enzymes usually are discovered when blood tests are performed as a part of an annual physical examination, as pre-operative screening, or as a part of periodic monitoring for drug toxicity. Typically, these abnormal levels will become normal shortly after stopping the drug, and there usually is no long-term liver damage. With some drugs, low levels of abnormal liver enzymes are common and don’t appear to be associated with important liver disease, and the patient may continue taking the drug.
Key Points About Drug
- Drug-induced hepatitis is a redness and swelling of the liver.
- It is a rare condition caused by harmful amounts of certain medicines, vitamins, herbal remedies, or food supplements.
- In most cases, you may be taking a medicine for several months before it reaches a toxic level and affects your liver.
- You may also get the condition if you take too much of some medicines, such as acetaminophen. This can happen quickly.
- You must stop taking the medicine that is causing the disease.
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